The international patent application WO 2010/143169 describes quinolin-2-yl-phenylamine derivatives which show inhibition of the production of the HIV core antigen p24 in HIV infected PBMCs (peripheral blood mononuclear cells). A once-day orally available first-in-class quinolin-2-yl-phenylamine derivative that inhibits HIV replication through this entirely new mechanism is (8-chloro-quinolin-2-yl)-(4-trifluoromethoxy-phenyl)-amine, also known as ABX-464. In contrast to the numerous antiviral drugs that are currently available for HIV treatment, this quinolin-2-yl-phenylamine derivative is the first agent that affects the production stage of HIV-1 replication by preventing the export of viral RNA from the nucleus to the cytoplasm in infected cells. Moreover, this drug candidate is highly selective and doesn't affect normal cellular splicing. Preclinical data indicated sustained reduction of viral load which lasted for several weeks after cessation of treatment. In phase I trials, it was well tolerated at dose levels up to 200 mg without clinically significant abnormal results. The drug candidate is currently in phase II evaluation.
The chemical structure of the drug candidate (8-chloro-quinolin-2-yl)-(4-trifluoromethoxy-phenyl)-amine, the molecular weight and formula are as follows:

WO 2010/143169 further discloses the preparation of quinolin-2-yl-phenylamine derivatives through two routes in the presence of a metal catalyst, such as Pd(OAc)2 or Pd2dba3. Example 5 describes the preparation of (8-chloro-quinolin-2-yl)-(4-trifluoromethoxy-phenyl)-amine (compound 90) according to route (A) and includes a final purification step by column chromatography to yield the pure compound.
The comparative example based on WO 2010/143169 shows that, although 2,8-dichloroquinoline was completely converted, the yield was limited to a maximum of 65%. It was further found by the inventors that simultaneous side reactions account for the relative low yield as they lead to undesired by-products. Moreover, the existence of these by-products makes pre-purification by flash chromatography inevitable. The results of the palladium mediated coupling according to Example 5 of WO 2010/143169 can be summarized as follows:

The rework of this procedure by the present inventors confirmed the compound, but since purification by column chromatography furnished the respective compound only in 95% purity due to undesired by-products, a recrystallization was further applied. Hereby the compound was obtained in a chemically pure crystalline form. Thereafter, the solubility of the compound was analyzed by the inventors in aqueous solutions with different pH-values simulating distinct physiological conditions. The outcome reveals a virtual insolubility of the compound in aqueous solution, independent of its pH value.
In view of the above and considering that reactions utilizing palladium as metal catalyst in the last stage are disfavored according ICH guidelines, an improved process for the preparation of quinolin-2-yl-phenylamine derivatives, and soluble forms or formulations of (8-chloro-quinolin-2-yl)-(4-trifluoromethoxy-phenyl)-amine are desired.
Therefore, the present invention concerns a process for preparing quinolin-2-yl-phenylamine derivatives, and soluble salts of (8-chloro-quinolin-2-yl)-(4-trifluoromethoxy-phenyl)-amine.